Relative effects of breastfeeding intention and practice on maternal responsiveness.

Our objective was to examine the differential effects of antenatal breastfeeding intention (BI) and breastfeeding practice (BP) on maternal postnatal responsiveness. We conducted a secondary analysis of longitudinal data from a subsample of 962 mother-infant dyads from a U.K.-based birth cohort study the Avon Longitudinal Study of Parents and Children. Exposures were BI and BPs measured at 32 weeks of gestation and 18 months' postpartum. The outcome was maternal responsiveness assessed at 12 months' postpartum. We used logistic regression analyses unadjusted and adjusted for confounders. Intention to breastfeed was associated with increased odds of postnatal maternal responsiveness independent of BP, adjusted odds ratio (OR) = 2.34, 95% CI [1.42, 3.86]. There was no evidence that BP was an independent predictor of maternal responsiveness, OR = 0.93, 95% CI [0.55, 1.57]. Life-course epidemiology analyses demonstrated that maternal responsiveness is most positive when both BI and BP are present. This is the first population-based study to provide evidence that BI during pregnancy is more strongly associated with maternal postnatal responsiveness than is BP. Further research is needed to understand the determinants of BI in pregnancy and its relationships with maternal responsiveness.

Propósito: nuestro objetivo fue examinar los efectos diferenciales de la intención antenatal de amamantar y la práctica de amamantar sobre la sensibilidad materna posnatal. Métodos: llevamos a cabo un análisis secundario de información longitudinal de un subgrupo muestra de 962 díadas madre-infante que eran parte de un estudio británico de cohorte de nacimiento, el Estudio Longitudinal Avon de Padres y Niños. Los aspectos de exposición fueron la intención de amamantar y las prácticas de amamantar según fueron medidas a las 32 semanas de gestación y 18 meses posparto. El resultado fue la sensibilidad materna evaluada a los 12 meses posparto. Usamos análisis de regresión logística sin ajustar y ajustados para factores de confusión. Resultados: se asoció la intención de amamantar con mayores probabilidades de sensibilidad materna posparto independiente de la práctica de amamantar (ajustada proporción de probabilidades (OR) 2.34, 95% CI 1.42, 3.86). No hubo evidencia de que la práctica de amamantar fuera un independiente factor de predicción de la sensibilidad materna (OR 0.93, 95% CI 0.55, 1.57). Los análisis epidemiológicos de curso vital demostraron que la más positiva sensibilidad materna se da cuando ambas, la intención de amamantar y la práctica de amamantar, están presentes. Conclusiones: este es el primer estudio con base en la población que aporta evidencia de que la intención de amamantar durante el embarazo está más fuertemente asociada con la sensibilidad materna posparto que la práctica de amamantar. Mayor investigación es necesaria para comprender los factores determinantes de la intención de amamantar durante el embarazo y sus relaciones con la sensibilidad materna.

But Notre objectif était d'examiner les effets différentiels de l'intention d'allaitement au sein avant la naissance et la pratique d'allaitement au sein sur la réaction maternelle postnatale. Méthodes Nous avons procédé à une analyse secondaire de données longitudinales à partir d'un sous-échantillon de 962 dyades mère-nourrisson d'une étude de cohorte de naissance britannique, l'Etude Longitudinale de Parents et d'Enfants de l'Avon. Les risques étaient l'intention d'allaitement au sein et les pratiques d'allaitement mesurées à 32 mois de grossesse et à 18 mois après la naissance. Le résultat était la réaction maternelle évaluée à 12 mois postpartum. Nous avons utilisé des analyses de régression logistique non ajustées et ajustées pour les facteurs de confusion. Résultats L'intention d'allaiter au sein était liée à des chances accrues de réaction maternelle postnatale sans lien à la pratique d'allaitement (rapport de cote ajusté (RCaj) 2,34, 95% CI 1,42, 3,86). On n'a trouvé aucune preuve que la pratique d'allaitement était un facteur de prédiction indépendant de la réaction maternelle (RCaj 0,93, 95% CI 0,55, 1,57). Les analyses d'épidémiologie du parcours ont démontré que la réaction maternelle est plus positive lorsque l'intention d'allaitement et la pratique d'allaitement sont présentes. Conclusions Voici la première étude sur une population qui présente des preuves que l'intention d'allaitement durant la grossesse est plus fortement liée à la réaction postnatale maternelle que la pratique d'allaitement. Des recherches plus approfondies sont nécessaires afin de comprendre les déterminants de l'intention de l'allaitement durant la grossesse et sa relation à la réaction maternelle.

Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog.

OBJECTIVE: Glucagon-like peptide (GLP)-1 is an incretin hormone that acts after food intake to stimulate insulin production, enhance satiety, and promote weight loss. Here we describe the discovery and characterization of ecnoglutide (XW003), a novel GLP-1 analog. METHODS: We engineered a series of GLP-1 peptide analogs with an alanine to valine substitution (Ala8Val) and a γGlu-2xAEEA linked C18 diacid fatty acid at various positions. Ecnoglutide was selected and characterized in GLP-1 receptor signaling assays in vitro, as well as in db/db mice and a diet induced obese (DIO) rat model. A Phase 1, double-blind, randomized, placebo-controlled, single (SAD) and multiple ascending dose (MAD) study was conducted to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous ecnoglutide injection in healthy participants. SAD doses ranged from 0.03 to 1.0 mg; MAD doses ranged from 0.2 to 0.6 mg once weekly for 6 weeks (ClinicalTrials.gov Identifier: NCT04389775). RESULTS: In vitro, ecnoglutide potently induced cAMP (EC50 = 0.018 nM) but not GLP-1 receptor internalization (EC50 > 10 µM), suggesting a desirable signaling bias. In rodent models, ecnoglutide significantly reduced blood glucose, promoted insulin induction, and led to more pronounced body weight reduction compared to semaglutide. In a Phase 1 trial, ecnoglutide was generally safe and well tolerated as a once-weekly injection for up to 6 weeks. Adverse events included decreased appetite, nausea, and headache. The half-life at steady state ranged from 124 to 138 h, supporting once-weekly dosing. CONCLUSIONS: Ecnoglutide showed a favorable potency, pharmacokinetic, and tolerability profile, as well as a simplified manufacturing process. These results support the continued development of ecnoglutide for the treatment of type 2 diabetes and obesity.

Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms.

Joint hypermobility is overrepresented among people with anxiety and can be associated with abnormal autonomic reactivity. We tested for associations between regional cerebral grey matter and hypermobility in 72 healthy volunteers using voxel-based morphometry of structural brain scans. Strikingly, bilateral amygdala volume distinguished those with from those without hypermobility. The hypermobility group scored higher for interoceptive sensitivity yet were not significantly more anxious. Our findings specifically link hypermobility to the structural integrity of a brain centre implicated in normal and abnormal emotions and physiological responses. Our observations endorse hypermobility as a multisystem phenotype and suggest potential mechanisms mediating clinical vulnerability to neuropsychiatric symptoms.

Nutritional perspectives on sickle cell disease in Africa: a systematic review.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder that predominantly affects individuals in sub-Saharan Africa. However, research that elucidates links between SCD pathophysiology and nutritional status in African patients is lacking. This systematic review aimed to assess the landscape of studies in sub-Saharan Africa that focused on nutritional aspects of SCD, and highlights gaps in knowledge that could inform priority-setting for future research. METHODS: The study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Inclusion criteria comprised original, peer-reviewed research published between January 1995 and November 2020 involving individuals in Africa with any phenotypic variant of SCD and at least one nutritional status outcome. Nutritional status outcomes were defined as those that assessed dietary intakes, growth/anthropometry, or nutritional biomarkers. Databases used were Ovid Embase, Medline, Biosis and Web of Science. RESULTS: The search returned 526 articles, of which 76 were included in the final analyses. Most investigations (67%) were conducted in Nigeria. Studies were categorized into one of three main categories: descriptive studies of anthropometric characteristics (49%), descriptive studies of macro- or micronutrient status (41%), and interventional studies (11%). Findings consistently included growth impairment, especially among children and adolescents from sub-Saharan Africa. Studies assessing macro- and micronutrients generally had small sample sizes and were exploratory in nature. Only four randomized trials were identified, which measured the impact of lime juice, long-chain fatty acids supplementation, ready-to-use supplementary food (RUSF), and oral arginine on health outcomes. CONCLUSIONS: The findings reveal a moderate number of descriptive studies, most with small sample sizes, that focused on various aspects of nutrition and SCD in African patients. There was a stark dearth of interventional studies that could be used to inform evidence-based changes in clinical practice. Findings from the investigations were generally consistent with data from other regional settings, describing a significant risk of growth faltering and malnutrition among individuals with SCD. There is an unmet need for clinical research to better understand the potential benefits of nutrition-related interventions for patients with SCD in sub-Saharan Africa to promote optimal growth and improve health outcomes.

The neuropsychological impact of insular cortex lesions.

Influential models based on an increasing body of neuroimaging evidence propose that insular cortex integrates cognitive, affective, sensory and autonomic information to create a consciously perceived, 'feeling state.' To appraise these models and evaluate interpretations of neuroimaging findings, the authors review evidence pertaining to the psychological and behavioural consequences of insula lesions. The authors focus on the emotional, perceptual, sensorimotor symptoms and disorders of body awareness associated with insula damage. This comprehensive review is intended to inform existing neuropsychological models of insula function in order to guide future research.

Drug Discovery for Kinetoplastid Diseases: Future Directions.

Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases.

A first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending oral dose study to assess the safety, tolerability, and pharmacokinetics of BZF961 with and without ritonavir in healthy adult volunteers.

Objective: Infection with hepatitis C virus is the leading indication for liver transplantation and most common cause of infectious disease-related mortality in the United States. BZF961 is a novel inhibitor of the hepatitis C virus NS3-4A protease. Methods: This sequential, three part exploratory first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of BZF961 in healthy subjects. The first two parts were randomized, double-blind, placebo-controlled, time-lagged, single and multiple ascending oral dose segments. The third part analyzed the effect of ritonavir on BZF961 pharmacokinetics. Results: BZF961 was generally safe and well-tolerated in single and multiple oral doses in healthy subjects. There were no deaths and no serious adverse events. The most common adverse events were nausea and other gastrointestinal symptoms. Co-administration of ritonavir with BZF961 was well tolerated and increased BZF961 exposure by up to 60-fold, as well as reduced the overall exposure variability. Conclusions: BZF961 was generally safe and well-tolerated and its exposure was boosted by the co-administration of ritonavir.

The Safety and Antiviral Activity of BZF961 with or without Ritonavir in Patients Infected with Hepatitis C Virus: A Randomized, Multicenter Trial.

PURPOSE: Infection with hepatitis C virus is the leading cause of infectious disease mortality in the United States. BZF961 is a novel small molecule inhibitor of the hepatitis C virus NS3-4A protease. Here we present the results of a randomized, double-blinded, placebo-controlled, multicentered study in treatment-naïve patients with chronic hepatitis C virus genotype-1 infection. METHODS: Patients were enrolled sequentially in 2 parts and treated for 3days. BZF961 was administered as monotherapy (500mg BID for 3 days) or in combination with the cytochrome P450 3A4 inhibitor ritonavir to boost its exposure (BZF961 10, 20, or 50mg QD or BID). FINDINGS: BZF961 was safe and well tolerated in the patients studied with no serious adverse events. There were no appreciable differences in adverse events among patients who received BZF961, BZF961 with ritonavir, or placebo. There was a significant, clinically meaningful reduction in viral load from baseline in patients treated either with BZF961 500mg every 12hours alone or BZF961 50mg every 12hours in combination with ritonavir. Activity against the hepatitis C virus of the lower-dose regimens was apparent but more modest. There were no relevant changes from baseline viral loads in placebo-treated patients. IMPLICATIONS: Coadministration of ritonavir with BZF961 boosted BZF961 exposure (including Cmin, which is the clinically relevant parameter associated with antiviral activity) in a therapeutic range with less variability compared with BZF961 alone. For strategic reasons, BZF961 is no longer under development.

Neuroanatomical substrates for the volitional regulation of heart rate.

The control of physiological arousal can assist in the regulation of emotional state. A subset cortical and subcortical brain regions are implicated in autonomic control of bodily arousal during emotional behaviors. Here, we combined human functional neuroimaging with autonomic monitoring to identify neural mechanisms that support the volitional regulation of heart rate, a process that may be assisted by visual feedback. During functional magnetic resonance imaging (fMRI), 15 healthy adults performed an experimental task in which they were prompted voluntarily to increase or decrease cardiovascular arousal (heart rate) during true, false, or absent visual feedback. Participants achieved appropriate changes in heart rate, without significant modulation of respiratory rate, and were overall not influenced by the presence of visual feedback. Increased activity in right amygdala, striatum and brainstem occurred when participants attempted to increase heart rate. In contrast, activation of ventrolateral prefrontal and parietal cortices occurred when attempting to decrease heart rate. Biofeedback enhanced activity within occipito-temporal cortices, but there was no significant interaction with task conditions. Activity in regions including pregenual anterior cingulate and ventral striatum reflected the magnitude of successful task performance, which was negatively related to subclinical anxiety symptoms. Measured changes in respiration correlated with posterior insula activation and heart rate, at a more lenient threshold, change correlated with insula, caudate, and midbrain activity. Our findings highlight a set of brain regions, notably ventrolateral prefrontal cortex, supporting volitional control of cardiovascular arousal. These data are relevant to understanding neural substrates supporting interaction between intentional and interoceptive states related to anxiety, with implications for biofeedback interventions, e.g., real-time fMRI, that target emotional regulation.

Under pressure: response urgency modulates striatal and insula activity during decision-making under risk.

When deciding whether to bet in situations that involve potential monetary loss or gain (mixed gambles), a subjective sense of pressure can influence the evaluation of the expected utility associated with each choice option. Here, we explored how gambling decisions, their psychophysiological and neural counterparts are modulated by an induced sense of urgency to respond. Urgency influenced decision times and evoked heart rate responses, interacting with the expected value of each gamble. Using functional MRI, we observed that this interaction was associated with changes in the activity of the striatum, a critical region for both reward and choice selection, and within the insula, a region implicated as the substrate of affective feelings arising from interoceptive signals which influence motivational behavior. Our findings bridge current psychophysiological and neurobiological models of value representation and action-programming, identifying the striatum and insular cortex as the key substrates of decision-making under risk and urgency.

Emotional modulation of visual cortex activity: a functional near-infrared spectroscopy study.

Functional neuroimaging and electroencephalography reveal emotional effects in the early visual cortex. Here, we used functional near-infrared spectroscopy to examine haemodynamic responses evoked by neutral, positive and negative emotional pictures, matched for brightness, contrast, hue, saturation, spatial frequency and entropy. Emotion content modulated amplitude and latency of oxy, deoxy and total haemoglobin response peaks, and induced peripheral autonomic reactions. The processing of positive and negative pictures enhanced haemodynamic response amplitude, and this effect was paralleled by blood pressure changes. The processing of positive pictures was reflected in reduced haemodynamic response peak latency. Together these data suggest that the early visual cortex holds amplitude-dependent representation of stimulus salience and latency-dependent information regarding stimulus valence, providing new insight into affective interaction with sensory processing.

MtuA, a lipoprotein receptor antigen from Streptococcus uberis, is responsible for acquisition of manganese during growth in milk and is essential for infection of the lactating bovine mammary gland.

A mutant strain of Streptococcus uberis (AJS001) that was unable to grow in bovine milk was isolated following random insertional mutagenesis. The level of growth in milk was restored to that of the parental strain (strain 0140J) following addition of MnSO(4) but not following addition of other metal ions. The mutant contained a single insertion within mtuA, a homologue of mtsA and psaA, which encode metal-binding proteins in Streptococcus pyogenes and Streptococcus pneumoniae, respectively. Strain AJS001 was unable to infect any of eight quarters on four dairy cows following intramammary challenge with 10(5) CFU. Bacteria were never recovered directly from milk of these animals but were detected following enrichment in Todd-Hewitt broth in three of eight milk samples obtained within 24 h of challenge. The animals showed no inflammatory response and no signs of mastitis. Three mammary quarters on two different animals simultaneously challenged with 600 CFU of the parental strain, strain 0140J, became colonized, shed high numbers of S. uberis organisms in milk, displayed a marked inflammatory response to infection, and showed overt signs of mastitis. These data indicate that mtuA was required for efficient uptake of Mn(2+) during growth in bovine milk and infection of the lactating bovine mammary gland.